M.D.-Ph.D. Program Harvard Medical School Winter 1994 Newsletter

Articles in this issue:

• Physician-Scientist: Paradigm or Paradox
• 100 Revel at Retreat

Physician-Scientist: Paradigm or Paradox

by David A. Shaywitz

"Sometimes I pinch myself - I'm doing what I've always wanted to do. Two of the things that make you feel best are making discoveries in lab and working with families of sick children. I get to do both." - Michael Kastan, MD/PhD, Department of Pediatric Oncology, Johns Hopkins. "Both science and medicine are so demanding - it is impossible to do both well. I think it is becoming increasingly clear that you have to do one or the other. It is important to collaborate closely - I think that physicians should understand science well enough to communicate with the scientists, for example, but I don't think they need to do PCR, etc., and similarly, I don't think that scientists need to draw blood and lay on hands." - David Botstein, PhD, Professor and Chair of Genetics, Stanford.

For many of us, the idea of an MD/PhD represents the elegant synthesis of two great passions - a love for the practice of science, and a love of the art of healing. Fundamentally, the dream many of us share is to be able to elucidate an essential biological process, and then apply this knowledge to the care and treatment of individual patients. This idea of conducting first-class basic research while maintaining a meaningful clinical interaction is obviously extremely appealing, and speaks of a synergy which in many ways is the organizing principle of the MD/PhD Program. However, while some of the best contemporary biologists are quite supportive of this paradigm, many others feel that it represents an unrealistic - and in some ways counterproductive - ideal.

Can you combine first-class research and be an excellent clinician? "No," argues Massachusetts Institute of Technology (MIT) cancer biologist Robert Weinberg. "It is a myth on which American academic medicine operates. It's a destructive myth; it encourages people to try something which is impossible to accomplish. Many people have excellent clinical skills and maintain a charade of meaningful research, but it is just that - a charade - and one which represents an enormous waste of resources. I can count on one hand the people who are doing excellent science and maintaining a foot in the clinical door; it just is not possible. Each of the two, individually, is too demanding."

However, others - such as developmental biologist H. Robert Horvitz - assert with equal vigor that "the answer is clear: absolutely yes." A basic scientist by training, Horvitz, who maintains one lab at MIT and is involved in a major collaborative effort at the Massachusetts General Hospital (MGH), feels that "given today's technology and knowledge, there is a need for people who understand medicine to be involved in research. There are medical problems that, for the first time, are tractable scientifically."

Researchers with a medical training are also divided on the usefulness of combining both interests. Harvard transplantation surgeon Joseph Murray, for example, asserts that, "It is absolutely essential that clinician-scientists have the same qualities of curiosity, imagination and persistence as the basic bench-scientists. The clinician can be a scientist, but the bench-scientist can never be a clinician. When you take care of patients, you become exposed to problems that are compelling, problems that are worth pursuing in the lab."

However, Stanford biochemist (and MD) Arthur Kornberg contends that "Doing clinical medicine properly - looking after patients in a meaningful way, keeping up with important advances, etc.- has a major negative effect on research. Clinical medicine generates an enormous number of ideas and opportunities; the multitude of them makes it even more distracting. One reason for the failure of many MD/PhD's is that they get distracted, and fail to focus on a narrow subject; they do a lot of little things."

Who is right? Is it possible to combine basic research and clinical medicine in a career, and if yes, then to what degree? Does the physician-scientist emerge from the long training as an "überdoktor", equally comfortable at the bench or the bedside, or as an over-educated, over-committed, and overwhelmed thirty-something who is, in the words of Weinberg, "a jack of all trades, but a master of none." These are very difficult questions for us to ask about ourselves, but also questions which each of us, at some level and at some point, will and must confront.

In the Beginning
The Medical Scientist Training Program (MSTP) was initiated by the National Institutes of Health (NIH) in 1964 as part of an effort to create a cohort of individuals who might bridge the perceived gap between bench researchers and clinicians. At present, the MSTP grant funds MD/PhD Programs at 32 universities, and supports approximately 800 students. A number of students also pursue both degrees without MSTP funding. For MSTP students nationally, the average time required to obtain the combined degree is approximately seven years; the average at Harvard is closer to eight years, with training periods of nine and ten years not unheard of.

As long as this route is, it is also very popular: last year, for example, over 300 students applied for 12 MD/PhD positions at Harvard. There are many reasons for this interest. For students committed to clinical medicine, the program provides an opportunity to develop a grounding in basic science, so that even if they will not be doing this type of research for their careers, they can still follow it, and perhaps more easily anticipate where advances in basic research might have important clinical implications. For students more interested in bench research, the program provides an opportunity to develop a familiarity with clinical issues, an understanding which might both inform the direction of research as well as suggest areas where a clinical implication might be pursued. Finally, for students interested in working in both realms, the program provides the basic education and vocabulary required to understand the needs and the resources of both the lab and the clinic. Traditionally, the first group of students move on to become "academic physicians," the second group, "basic scientists," and the third group, "physician-scientists."

When the combined degree program first started, it was greeted with some skepticism by clinical faculties. "They took awhile to come around," says Lee Van Lenten, Director of the National Institute of General Medical Sciences, the NIH division which oversees the MST Program. "Their concern was that for the combined degree students, the PhD was the primary motivation, and the MD was second. So, the worry was that these students couldn't be well-trained - clinically - because they were not interested." At present, however, this concern seems to have dissipated; MD/PhD students compete quite successfully for both residencies and medical school faculty appointments. In general, MD/PhD graduates have found themselves welcomed by academic medicine, and the PhD training is often seen as useful, as time well spent.

Some bench scientists are equally enthusiastic about the combined degree program. "My feeling is that the future is with the MD/PhD students," University of Washington geneticist Leland Hartwell explains. "They'll make a difference in ten years. There is a real place for the MD/PhD. It is a very demanding, very anxiety-ridden route, but having a real medical training, and then doing a rigorous PhD, is a truly valuable and worthwhile investment."

Adds Hartwell, "Many graduate students in basic science feel that there aren't new niches in which to establish one's self. Where are there niches? I suspect there are more niches available in clinically-related areas. If you want to study a basic problem in yeast cell biology, don't bother with the MD. But, if your calling is to interface, then pursue it in the most fundamental way. Relax, take the long course, and don't worry about it. Be confident that because of the long-term investment and unique vision, you'll get there - because you're the only one who can get there."

Not all bench scientists share this perspective, however. Many feel that a career in basic science is, in general, incompatible with almost any clinical responsibilities. They argue that if individuals want to get dual training, and to apply advances in basic research to problems in the clinic, fine; this research (the reasoning goes) may be good research, may be important research, but it is not basic research. Furthermore, if individuals with dual training want to devote themselves to basic research, with no clinical responsibilities, this also may be reasonable; the cost in time of the additional training may be balanced by the additional perspective the clinical training affords. However, if MD/PhD graduates actually intend to combine basic research with a clinical interaction, the argument continues, they are going to set themselves up for disappointment, both because basic research is now too demanding to be combined with anything else, and because clinical medicine does not, in practice, synergize with basic research, but only detracts from it.

The Four Questions
In essence, the major arguments against conducting basic research while maintaining a clinical interaction are: (1) the long training period detracts from optimal research time; (2) bench research requires absolute focus; (3) no one can maintain two different careers; (4) clinical medicine and bench science are fundamentally different, and are not mutually reinforcing. These objections will be considered individually.

I: The Long and Winding Road
The long period of training required for MD/PhD's represents, to many researchers, the most significant potential pitfall for MD/PhD students. In the words of Marjorie Oettinger, who is a biologist at the MGH (and who was initially in the Harvard/MIT MD/PhD Program but departed, after completing the PhD, to start her own lab), "I started out quite sure I wanted to do both, and quite sure I could do both; it seems less easy now. At 20, you're sure that you'll be awesome, that you'll have an infinite amount of time and skill, and that you will push your career as much as possible. Along the way, you realize as you do research - and do it seven days a week, sixteen hours a day, and it's still going slowly - and you think `I'd also like to have kids; I'd also like to do medicine' - and you start counting the years."

"My major concern about the [MD/PhD] Program is the time it takes," agrees MIT biologist Phillip Sharp, whose lab has trained many MD/PhD students. "The program is very expensive in time. I don't like the idea that people emerge ready to do mature science at age 35, and not 27 or 28. These are the most scientifically productive years - immediately after training, while you're developing as a young person, with energy, intensity. If you displace out to 35, you have older families, greater responsibility. If that's the first time you're scientifically independent, it's late."

Rockefeller University biologist David Baltimore expresses similar feelings: "I think people should make the decision when they graduate from college," he says. "I think it's fine to choose an MD/PhD Program if you decide you truly need both kinds of education, but I think that most people enter the Program because they are avoiding the decision. In avoiding the decision, they are wasting the best years of research life."

Baltimore adds, "Most people make their major contributions in their 30's, and so it's important for scientists to be independent in their 30's. Since MD/PhD's don't really become independent until their late 30's, this is a great loss of time. Also, because they're older, they're less likely to take the long-term perspective; in a sense, their desire is `too' burning. If you can decide very early on a biological system to study, and become familiar with it in depth and at leisure, you're more likely to eventually develop something of deep biological importance."

Many physician-scientists, however, counter that the time issue is exaggerated, greatly. "When I applied to medical school" MGH neurologist/neuroscientist Anne Young relates, "the Harvard recruiter told me, we don't believe in MD/PhD Programs - they take much too long. Well, I went somewhere else - Johns Hopkins - and was on the faculty by 30, had my first grant at 30, and had published 40 papers by 33. You can find MD/PhD's who are productive early on." Adds Young, "The idea that graduates of the program are pushing senility is specious beyond belief. It shows great naivete. Just look out there."

Observes Arlene Sharpe, a member of the Harvard pathology department who runs the core transgenic facility at Brigham and Women's Hospital (BWH), "It is a long road, but you get a unique perspective. The PhD gives you the intellectual background and thought processes needed to be a scientist, while the MD provides the broad background in which to do research. Also, although most MD/PhD's don't reach independence until their mid 30's, I found that doing both taught me how to juggle."

II. A Need to Focus
To many scientists, a career of basic research requires absolute focus, and none of the "distractions" which clinical medicine represents. "Contribution to basic science," explains Sharp, "requires a set of colleagues intellectually involved in that activity. Information flows - students come with information, talk about what is going on at the forefront; they have nothing else to do but talk and read about it, no `higher purpose.' They're not worried about responding to a call, they're not worried about internship/residency/placement. Their only objective is to be a scientist - they are that focused."

"If you want to be successful in basic science," explains Linus Pauling - the chemist who in 1949 first coined the term "molecular disease" - "you probably have to devote all your time, all your thinking to it. You can't do this if you have patients - the primary responsibility of physicians is to take care of patients. If you want to discover the double helix, you can't do it while practicing clinical medicine."

Yet, many physician-scientists worry that by maintaining a restrictive focus, many bench researchers may ignore larger questions, and not always appreciate the "big picture."

"What is science," Anne Young asks, "and why must good science be done in isolation? What does it mean to find a growth factor in tissue culture? It is a narrow view that there doesn't exist any science between the discovery of a growth factor and the treatment of the actual disease. To say that the discovery of a new factor is the only intellectually challenging goal is absurd. The understanding of how the factor plays a role in a multi-cellular system should not be viewed as less important. People have trouble differentiating between asking a scientific question about how something happens in disease from running a new drug trial."

Agrees Murray, "Someone can devote 100% of the time to bench science but often may not detect the big picture. Society needs clinician-scientists. Many successful treatments of disease, (e.g. kidney, heart, some cancers) have resulted only because clinicians have pursued basic science."

Children's Hospital pediatric hematologist Stuart Orkin, a physician-scientist who attends on the wards one month a year, feels that although, in practice, the bedside "rarely" informs the bench, and although he has received "very limited insight from the wards," the MD/PhD's nevertheless possess a perspective that is "different." Orkin says that in his lab, the post-docs with MD/PhD's "seem, in general, to be intellectually more mature, to have a more global sense of biology, of where things fit, but they may be less equipped to do the actual experiment. By contrast, the PhD's are often better able to do the experiment, but they are less able to formulate how it fits in."

"It's a trade off," explains Harvard geneticist Philip Leder. "Clinical involvement takes time from full-time research, but it provides insight into nature, provides a broad view of human biology and pathology." However, Leder also believes that MD/PhD's "have to make an unpleasant decision at some point," and adds that "the most successful MD/PhD researchers I've seen aren't ambivalent - they get right on to it."

III. Dual Training vs. Dual Career
Many scientists - and particularly, many physician-cum-scientists - consider the clinical training useful, but the combined career unrealistic. "Clinical experience was a motivating force," says Johns Hopkins cancer biologist Bert Vogelstein, who began a post-doc (at age 26) after two years of residency. "It familiarized me with biology as well as the clinical dimension of illness. It is difficult to become intimately familiar with human disease unless you study all aspects of it. Medical school familiarized me in a way which would have been difficult otherwise." However, Vogelstein cautions that "research is a full-time activity, and to stay clinically active demands substantial time. It would be great if you could see patients and conduct research, but there are only eighteen hours a day you can work - time becomes limiting." Vogelstein - who gave up clinical medicine when he entered the lab - adds that "in general, it's not realistic to do both - it's impossible to do two careers at once, except under very special circumstandes."

Agrees Stanford geneticist David Botstein, "I think it's reasonable to obtain both educations, but not to pursue both careers."

Even University of Texas-Southwest Molecular Genetics Chair Joseph Goldstein, who is often cited as a model physician/scientist, says "It's harder and harder for someone to do both. Science is a tough world, and things move very fast. You can do ten to twenty times more now than what you could twenty years ago. To be competitive at the forefront of science, you must put everything you have into it. If you want to do cutting edge research, it will be almost impossible to be a credible clinician. There is no way to be at the top of your field in basic science without spending 95% of your time thinking about it and doing it. You can't be a researcher at the forefront and still be responsible for - and responsive to - patients who call you up."

Adds Alan D'Andrea, a hematologist/oncologist at the Dana Farber Cancer Institute, "There are very few physician-scientists who are doing forefront research, on the cutting edge, and are still seeing patients."

Yet, many physicians and scientists argue that the two career option, while not easy, is achievable. "Nothing is impossible - just difficult," Johns Hopkins biochemist Daniel Nathans asserts. "You must take patient responsibilities seriously. The key is to select a very specialized clinical interest, related to your area of research. There is some advantage - in terms of personal satisfaction - for people who try to do it all in some narrowly defined area. You don't need to spend 100% of your time at the bench, or even thinking about research, but you must spend a good fraction of your time at it. It really depends upon your motivation." Nathans continues, "You must ask what you want to do with your life, what gives you satisfaction. If it's both patients and research, then you should try your hardest to do both. It is difficult, but possible for highly talented, highly motivated people."

"Doing both is highly possible," agrees NIH Deputy Director Ruth Kirschstein. "Lots of graduates wind up in medicine departments, and do very meaningful research which has some relationship to their clinical activities."

Robert Glickman, Chair of Medicine at the Beth Israel Hospital, asserts that "doing both is possible under very discrete circumstances. You must concentrate in one area or the other. You can do 20% non-research activity, whether administrative, teaching, or patient care - but only in a specialty area, where it is possible to do focused and concentrated work. You need a support system. I think you must set the clear, clear, clear expectation that you'll spend the dominant part of time doing research. Focus on a concentrated area, and don't get diverted."

IV. An Elusive Synergy
One of the most persistent critiques made by basic researchers centers on the idea of cross- fertilization between the lab and the clinic. "The idea that basic science and clinical medicine are complementary is naive," says MIT cancer biologist Tyler Jacks, who was (briefly) a member of University of California, San Francisco's MD/PhD program before deciding on a career of full-time research. Jacks continues, "the bench and the bedside involve radically different things. The kinds of skills you need on the wards don't apply to the study of the cancer cells in the tissue-culture dish, for instance. There are examples where careers were launched by identifying a problem in disease and approaching it from the molecular or cellular point of view. But crosstalk once you've made the decision to pursue basic science? I think not."

This synergy "rarely materializes" David Baltimore agrees, adding, "There is a real dissociation between science and medicine; the work occurs at a different level. Medicine is the solution of pressing problems with insufficient information, and science is more or less the opposite; you have the time to get the information."

Adds Jacks, "Some people have active labs as well as clinical responsibility; they do it because they enjoy it, because they get satisfaction from it; in general, they don't do it because the kinds of information they receive directly benefits their research. However, there is a sacrifice involved in maintaining the clinical work."

Such arguments upset many physician-scientists, including Dr. Young. "These people have never done clinical medicine, and have no basis for judgement," she contends. "It's such a narrow view of science and of medicine. They don't acknowledge that the way science in the lab can be brought close to humans and human disease is by people who know how to interface. For example, you can find protein processing pathways for intracellular signalling systems, but you need to ask, `what is it relevant for?' You must have insight into human disease, to know how to ask the questions. The idea that clinical medicine has no scientific basis is based on lack of experience and exposure; this is what we need to teach students, that patients teach you things. Only when you get to a certain stage (of either research or clinical work) do you realize that you need the other side. You need to have people at the interface."

"The idea of going from bench to bedside and bedside to bench came from an era before molecular biology, the era of metabolic studies," Kirschstein points out. "Now, doing molecular biology doesn't require you to be two feet from the patient. However, your clinical experience still gives you an improved understanding of the patient's disease, and of the basic processes which underlie it."

Agrees Dominick Purpura, Dean of Albert Einstein College of Medicine, "PhD's who are only in the lab can't make the connection with clinical problems. There is information to be gained by observing the natural course of disease."

In Part II, we will speak to Johns Hopkins oncologist Michael Kastan, UCSF virologist Don Ganem, and Harvard neurologist Stuart Lipton - three physician-scientists who are trying to integrate very productive bench research with an interest in and a commitment to patient care. We will also consider alternatives to the combined degree program - programs or classes that provide graduate students who have an interest in clinical questions with the opportunity to develop a greater familiarity with medicine without spending four years in an MD program.

David Shaywitz, a fifth-year M.D.-Ph.D. student, studies protein sorting in the laboratory of Chris Kaiser, Department of Biology, MIT.

100 Revel at Retreat

by Joel Pomerantz

The Annual Retreat has traditionally been a vivid reminder of the diversity of research interests in the M.D.-Ph.D. Program and this year's was no exception. Friday night presentations kicked off the scientific discussion with a series of witty and attractive 5th year students who introduced the breathless audience to topics as varied as the entropic cost of ligand association, the mechanisms of protein targeting and secretion, and exon shuffling. The reception that followed was the first opportunity for attendees to get reacquainted. Looking through the crowd, one student recognized representatives from most stages of M.D.-Ph.D. training and noted that the retreat was one of the few events at which generic progress through the program was made tangible.

The scientific presentations were raised to another level on Saturday as senior students served up a meaty smorgasbord of data and style. Asa Abeliovich described the use of knock-out mice in the study of learning and memory, while Bill Hahn presented the functional modularity of the T cell CD2 molecule. These were followed by Serge Jean, who explored different mechanisms of Herpes Virus gene regulation, and Saechin Kim, who delivered an earthy talk about programmed cell-death in worms. The final two talks of the morning surprised most of the audience. After catching attention with several slides displaying anomalies of the male genitalia, Vernon Rosario illuminated society's use of stigmata to categorize and stratify its members and the role of the "scientist" in establishing the "objectivity" of this practice. Still recovering from Vernon's talk, the audience then received a handout from Frank Rybicki, who proceeded to make magnetic resonance imaging ridiculously simple while explaining his efforts to develop a novel ultrafast MRI technique. Among Frank's insights was the possibility of performing a Fourier transform with respect to a potato. Many were glad to then have a few hours of rest after such a stimulating morning.

The afternoon poster session provided a forum for informal exchange among students and faculty and served to put on display the breadth and quality of research that is pursued by members of the program in every class year. During this time, many described an intensifying anticipation for Dr. Peter Howley's invited faculty talk and the subsequent distribution of the new M.D.-Ph.D. Retreat T-shirt, designed by Cindy Wang. Neither disappointed. Dr. Howley educated many with a data-rich discussion of the carcinogenic properties of Human Papillomavirus gene products and their relationship to normal cellular growth control. This was the point in the retreat when students were perhaps most clearly reminded of the potential for basic research to impinge upon important clinical problems while advancing understanding of basic human biology.

The traditional Saturday night festivities officially began with a Top Ten List expertly delivered by Linda Burnley. NBC representatives in the audience were said to make an immediate offer to Burnley to replace Conan O'Brien as the Late Night host, while rumors alleged that she is patiently holding out for the Letterman job. The applause carried over to the traditional party and dance at the Woods Hole MBL Club, where a selection of dance favorites got many to move and groove and some to disrobe. As the grogginess gradually wore off Sunday morning, Alice Flaherty and Walter Ralph provided the scientific finale for the retreat, presenting respectively on sensorimotor processing in the basal ganglia and the role of 5' untranslated sequences in gene regulation.

The weekend's finale was the First Annual Lobster Clambake which provided a festive ending to this year's retreat as well as inspiration and food for thought as conversations turned to ideas for next year's gathering.

Joel Pomerantz is an M.D.-Ph.D. candidate in Biology at MIT.

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